Process for preparing mercapto butyric acids



PROCESS FOR PREPARING MERCAPTO BUTYRIC ACIDS Arthur F. Wagner, Princeton, N. J., assignor to Merck & Co., Inc., Railway, N. J., a corporation of New Jersey No Drawing. Uriginal application July 21, 1953, Seriai No. 369,535. Divided and this application December 30, 1954, Serial No. 473,926

5 Claims. (Cl. 260526) This invention relates to 5-[3-(1,2-dithiacyclopentyl)] entanoic acid. More particularly, it is concerned with the preparation of novel a -[hydrocarbon substituted mercapto] butyric acids which are useful as intermediates in the synthesis of 5-[3-(1,2-dithiacyclopentyl] pentanoic acid, and processes for preparing the same.

This application is a division of my application Serial No. 369,535, filed July 21, 1953.

5-[3-(1,2-dithiacyclopentyl)] pentanoic acid is a growth stimulating crystalline substance first isolated from liver and originally called Ot-llPOlC acid. This substance was found to have the structure and was given the common name: 6-thioctic acid, as is disclosed in the I. Am. Chem. Soc., 74, 3455 (1952). Although 5-[3-(1,2-dithiacyclopentyl)] pentanoic acid can be isolated from natural materials such as liver, the difficulties encountered and low yields obtained have indicated the need for a practical synthetic method of producing the desired product.

Therefore, an object of this invention is to provide novel compounds useful for the synthetic production of 5-[3- (l,2-dithiacyclopentyl)] pentanoic acid. A further object is to provide processes for preparing these novel compounds.

According to one embodiment of the present invention novel a,) -biS [hydrocarbon substituted mercapto] butyric acids are provided having the formula:

SR wR wherein R is a hydrocarbon radical such as alkyl, alkenyl, aryl or aralkyl group together with processes and intermediates useful for preparing the same. These compounds are useful in the synthesis of -[3-( l,2-dithiacyclopentyl)] pentanoic acid.

The novel (y-bis [hydrocarbon substituted mercapto] butyric acids are produced by reacting an my-dihalobutyric acid with an ammonium, alkali metal or alkaline earth metal hydrocarbon mercaptide to form the corresponding ammonium, alkali metal or alkaline earth metal salt of the or,'y-bis [hydrocarbon substituted mercapto] butyric acid and subsequently hydrolyzing the salt to the corresponding coy-bis [hydrocarbon substituted mercapto] butyric acid. This reaction may be conveniently illustrated as follows:

CHr-OHr-CH-COOH I l YSR X x (fHrCHwOH-COOY F oHtoH2oH- oooH SR on T in p R wherein X is a halogen, Y is ammonium, an alkali metal or alkaline earth metal, and R is a hydrocarbon radical .such as an alkyl, alkenyl, aryl or aralkyl group.

The ammonium, alkali metal and alkaline earth metal salts of un -bis [hydrocarbon substituted mercapto] butyric acids are conveniently produced by reacting the theoretical amount of about three molar equivalents of the corresponding ammonium, alkali metal or alkaline earth metal hydrocarbon mercaptide with one molar equivalent of an a,'y-dihalobutyric acid. Although this ratio of reactants has been found most satisfactory, other ratios including an excess of either reactant may also be employed if desired. 7

The reaction may be conveniently achieved by contacting the mercaptide and 01.,7-dlh3l0blltYIlC acid either in the presence or absence of an added solvent. In this regard, high yields of the desired product may be obtained by either of these methods. However, when the use of a solvent is desired inert organic solvents such as chloroform, carbon tetrachloride, toluene and lower alcohols may be employed with satisfactory results. In addition, water may be present in small amounts without adverse effect. Temperatures from about 0 C. to about C. are suitable for effecting the reaction. However, the lower reaction temperatures are ordinarily preferred for effecting the reaction in the presence of a solvent while higher temperatures are employed when the reaction is carried out in the absence of a solvent.

The reaction is completed in a relatively short time, an hour being generally sufficient under ordinary circumstances. When the reaction has been completed the corresponding ammonium, alkali metal or alkaline earth metal salt of na y-bis [hydrocarbon substituted mercapto] butyric acid may be recovered by conventional methods or converted directly to the free acid according to the succeeding step. Examples of salts which may be prepared according to this process from the corresponding mercaptides drolysis. This reaction may be conveniently accomplished by acidifying the reaction mixture from the previous step with a suitable acid, preferably a mineral acid such as phosphoric acid, hydrobromic acid, hydrochloric acid and the like. The product may then be isolated from the reac-' tion mixture by conventional means such as extraction or fractional distillation.

Illustrative of the overall process forming part of this invention is the production of a,'y-bis[methylmercapto] butyric acid by reacting a,'y-dibromobutyn'c acid with sodium methylmercaptide to produce sodium-a -bis- [methylmercapto] butyric acid which is hydrolyzed with hydrochloric acid to a y-bis [methylmercapto] butyric acid. Examples of other similar compounds which may be produced according to this process are can-bis [ethylmercapto] butyric acid, a,'y-bis[propylmercapto] butyric acid, a,y-bis- [butylmercapto] butyric acid, a,'y-bis[amylmercaptol butyric acid, a;y-bis[allylmercapto] butyric acid, a,'y-bis- [3,S-dimethyl-Z-heptenemercapto] butyric acid, oc,'y-blS[2- methyl-l-ethyl-Z-butenemetcapto] butyric acid, uyy-bis 3- methyl-2-ethyLZ-pentenemercapto] butyric acid, urn-bis- [phenylmercapto] butyric acid and m,- '-bis[benzylmercapto] butyric acid. 7

The uyy-dihalobutyric acids which are used as starting 'materials in this invention may be're adily prepared by I of an added solvent. However, some solvents which may Patented July 8, 1958 be used if desired are chloroform, carbon tetrachloride, benzene and hexane. The a,'y-dihalobutyric acid formed according to this reaction may be used in the process of this invention as present in the reaction mixture or after its isolation therefrom by conventional methods. With regard to the present invention best results are obtained when a; -dichlorobutyric acid or aq-dibromobutyric acid is used as the starting material.

Examples of ammonium, alkali metal and alkaline earth metal hydrocarbon mercaptidcs which r -.y be in this invention to produce the correspc-t ing :,",iI)iS- [hydrocarbon substituted mercaptol butyric acids are sodium methylmercaptide, magnesium ethylmercaptide, potassium .propylmercaptide, calcium butylmercaptide, .sodium phenylmercaptide, potassium benzyhncrcaptid-z. am monium methylmercaptide, potassium allylmercaptide, sodium 3,5-dimethyl-2heptenemercaptide, sodium 2- methyl-l-ethyl-2-butenemercaptide, potassium 3-methyl-2- ethyl-Z-pentenemercaptide, and the like. The sodium and potassium salts of the respective mercaptides are preferred for use in the described reaction.

Also included within the purview of this invention are the esters of a,'y-bis[hydrocarbon substituted mercapto] butyric acids. In this regard, alkyl, aryl and aralkyl esters may be produced by reacting an a,'y-bis[hydrocarbon substituted mercapto] butyric acid with a halogenating agent to form the corresponding acyl halide and subsequently reacting the acyl halide with an alkanol, aryl alcohol or aralkanol to obtain the desired ester. This halogenation may be conveniently accomplished by reacting the 0c,"y-biS- [alkyl, alkenyl, aryl or aralkyl mercapto] butyric acid, or an alkali metal salt thereof, with a suitable halogenating agent. Examples of halogenating agents which may be used are thionyl chloride, oxalyl chloride, phthalyl chloride, phosphorous trichloride and the like. The reaction is readily achieved in a liquid medium formed by using either an excess of the halogenating agent, when liquid, or an added inert organic solvent. Temperatures of about 010 C. are ordinarily suitable for efiecting the reaction although higher temperatures may also be used. After the reaction has been completed the aq-bislhydrocarbon substituted mercapto] butyryl halide is recovered according to the conventional procedures. Representative of the acyl halides produced in this manner are orgy-bis- [methylmercapto] butyryl chloride, aq-bislethylmercapto] butyryl bromide, ow-bislallylmercaptol butyryl chloride and the like.

The a,- -bis[hydrocarbon substituted mercapto] butyryl halides produced as above may be conveniently esterified by reacting the acyl halide with an excess of an alcohol corresponding to the ester desired. Thus, by reacting u,- -bis[methylmercapto] butyryl chloride with methanol the corresponding methyl ester is obtained. Examples of other esters which are prepared in a like manner are ethyl- -bis[methylmercapto] butyrate, propyl-a,' -bis[ethylmercapto] butyrate, butyl-a, -bis[propylmercapto] butyrate, methyl-o 'y-bis[ethylmercapto] butyrate, benzyl-o bislmethylmercapto] butyrate, rnethyl-a,'y-bis[allylmercapto] butyrate, methyl-aq-bis[phenylmercapto] butyrate and ethyl-a,' -bis[benzylmercapto] butyrate.

In addition, lower alkyl esters may also be produced by reacting an v-bisEhydrocarbon substituted mercaptol butyric acid with a diazoalkane, such as diazomethane or diazoethane, in a suitable dry inert solvent such as ether, chloroform, benzene and the like. The resulting esters, like the acids, are water insoluble oils which may be purified by distillation under reduced pressure.

The orgy-bis [hydrocarbon substituted mercapto] butyric acids provided by this invention are useful in the production of -[3-(1,2-dithiacyclopentyl)] pentanoic acid, also called cz-lipoic acid; One such method for producing 5-[3-(1,2-dithiacyclopentyl)] .pentanoic acid, which process however, is not part of the present invention, being the invention of Holly Walton, Wagner and Hoifman,

iii

Serial No. 396,334, filed December 4, 1953, comprises reacting an a,'y-bis[hydrocarbon substituted mercapto] butyryl halide with a tert.-butyl ethyl malonic acid dicster a, ethoxymagnesium derivative in an anhydrous solvent, adding water and acid to the reaction mixture to convert the resulting Grignard complex to a tert.-butyl- 4,6-bis [hydrocarbon substituted mercaptol-Z-carbethoxy- 3-oxocaproate, treating said compound with p-toluenesulfonic acid to produce an ethyl-4,6-bis[hydrocarbon subst tuted are.captoj-l -oxocaproate, reacting said compound with methyl fi-chloropropionate to form a methyl- 6,8-bis[hydrocarb0n substituted mercapto]-4-carbethoxy- 5-oxocaprylate, deesterifying and decarboxylating said compound with a mixture of glacial acetic acid and hyoric acid to obtain 6,8-bisEhydrocarbon substituted 'aptol-5-oxocapry1ic acid, reducing said compound with sodium borohydride to the corresponding S-hydroxy caprylic acid which immediately forms a 6,8-bislhydrocarbon substituted mercaptol-S-hydroxy caprylic acid 5- lactone, reacting said lactone in glacial acetic acid containing phosphorus and iodine to produce 6,8-bislhydrocarbon substituted mercapto] butyric acids which may be used according to this synthesis of ix-lipoic acid are those in which the hydrocarbon substituent is an alkyl, alkenyl, aryl or aralkyl group such as the methyl, ethyl, allyl, benzyl and phenyl radicals.

According to a further embodiment of this invention compounds having the formula wherein R is a hydrocarbon radical such as an alkyl, aryl, or aralkyl group and R is an alkyl group, may be produced according to an additional novel process. These compounds are also useful intermediates in, the synthesis of 5-[3-(1,2-dithiacylclopentyl)] pentanoic acid, or a-lipoic acid.

Compounds having the described formula may be conveniently produced by reacting an e-hnlo-' -butyrolactone with an ammonium, alkali metal or alkaline earth metal hydrocarbon mercaptide to produce an a-hydrocarbon substituted mercapto-v-butyrolactone, reacting said compound with an ammonium, alkali metal or alkaline earth metal alkyl mercaptide to produce the corresponding ammonium alkali metal or alkaline earth metal alkyl mercaptide addition product of the a-hydrocarbon substituted mercapto- -butyrolactone and heating said.

addition compound to produce the desired product. This process may be represented structurally as follows:

wherein X represents a halogen, Y is ammonium, an alkali metal or alkaline earth metal and R is a hydrocarbon such as an alkyl, aryl or aralkyl group and R is an alkyl group.

The production of whydrocarbon substituted mercaptov-butyrolactones is readily accomplished according to the first step of this process by reacting approximately one equivalent of an ct-halowbutyrolactone with about one equivalent of an alkali metal or alkal e earth metal hydrocarbon mercaptide. This reaction may he conveniently achieved by contacting the reactarts in a suitable inert organic solvent such as the lower alcohols, hexane. benzene, toluene and inert chlorinated solvents such as chloroform and carbon tetrachloride. The reaction is exothermic in nature and to prevent overheatingthe reactants are generally combined slowly and the mixture cooled by suitable means. In this connection, it is preferred to maintain a reaction temperature below 60 C..

to prevent destruc tion of the reactants and the product. Usually an hour or so is sufficient to' complete the reaction after which the product may be recovered from the reaction mixture by conventional methods. One such method comprises evaporating the solvent and purifying the product by extraction and fractional distillation.

tit-Hydrocarbon substituted mercapto-y-butyrolactones which are produced according to this process are ot-alkyl, aryl and aralkyl mercapto-y-butyrolactonessuch as amethylmercapto-y-butyrolactone, ct-GthYltHfifCtPtO-w-btltyrolactone, a-propylmercapto-' -butyrclactone, a-phenylmercapto-y-butyrolactone and ct-benzylmercapto- -butyrolactone.

The u-halo-y-butyrolactones used as starting materials in this process may be prepared by the application of methods described in U. S. Patent No. 2,530,348 and the J. Am. Chem. Soc. 67, 2218 (1945). Specifically, O" chloro-y-butyrolactone and u-bromo-q butyrolactone are particularly suitable for this purpose.

Representative of the ammonium, alkali metal and alkaline earth metal hydrocarbon mercaptides which may be used as starting materials are the ammonium, sodium, potassium, lithium, calcium and magnesium salts of methylmercaptan, ethylmercaptan, butylmercaptan, phenyhnercaptan and benzylmercaptan. I

In the second step of this process the tat-hydrocarbon substituted mercaptow-butyrolactones are reacted with approximately one equivalent of a suitable ammonium, alkali metal or alkaline earth metal alkyl mercaptide to produce the corresponding ammonium, alkali metal or alkaline earth metal alkyl mercaptide addition product of the rat-hydrocarbon substituted mercapto-' -butyrolactone, This reaction is conveniently conducted in the presence of an'inert non-hydroxylic solvent such as hexane, benzene, chloroform and the like. The addition product forms readily at ordinary temperatures and may be recovered from the reaction mixture by removing the solvent.

Examples of addition products which may be produced in this manner are the sodium methylmercaptide addition product of a-methylm'ercapto-y-butyrolactone, the potassium ethylmercaptide addition product of a-methylmercaptoq-butyrolactone, the sodium methylmercaptide addition product of ot-benzylmercapto- -butyrolactone and the like.

Ammonium, alkali metal and alkaline earth metal alkyl mercaptide addition products of ot-alkylmercapto'w butyrolactones may also be prepared according to a one step process, rather than according to the two step method previously described, by reacting directly about two equivalents of a suitable ammonium, alkali metal or alkaline earth metalalkyl mercaptide with one equivalent of an a-halo-'y-butyrolactone.

According to this reaction the products produced have identical mercapto substituents, i. e., R=R', and are therefore useful intermediates in preparing a,'y-bis[alkylmercapto] butyric acids. The production of these addition products may be conveniently achieved according to the reaction conditions described above for the production of such compounds in two steps.

The ammonium, alkali metal and alkaline earth metal alkyl mercaptide addition products of (x -hydrocarbon substituted mercapto- -butyrolactones are converted to the corresponding int-hydrocarbon substituted mercaptoalkyl mercapto butyric acids according to the next step of this process by heating the addition product at an elevated temperature. For this purpose, temperatures of about ISO-200 C. are satisfactory although it is preferred to effect the reaction at about 170 C. At such temperatures the reaction goes to completion in about one hour. The product forms as an alkalimetal or alkaline earth metal salt which may be conveniently recovered or ethylmercapto butyric acid, a-propylmercapto-y-ethylmercapto butyric acid and wbenzylmercapto- -methylmercapto butyric acid may be produced from the appropriate 'butyrolactone addition product. Salts and esters of these and similar compounds may be produced by the methods previously described herein. Furthermore, these compounds may be used in the production of 5-[3-(1,2-dithiacyclopentyl)] pentanoic acid by the procedure referred to prior hereto.

The following examples are included to illustrate specific embodiments of this invention.

EXAMPLE I Production of aywbis[methylmercaptO] butyric acid To a solution of 77 gm. of sodium methoxide in 750 ml. of cold anhydrous methanol is added gm. of methylmercaptan. The mixture is stirred while cooling by means of an ice bath. To the resulting solution of sodium. methylmercaptide is added gm. of ot-y-dibromobutyric acid. The a,'y-dibromobutyric acid is added dropwise over a period of 15 minutes during which the temperature of the reaction mixture rises to about 30-40 C. The reaction mixture containing the sodium salt of orgy-bis [methylmercapto] butyric acid is concentrated to a small volume by evaporation on a water bath under reduced pressure, 500 ml. of water is added and the pH adjusted to 3 with hydrochloric acid. The a,'y-bis[methyhnercapto] butyric acid separates and is extracted with chloroform. The chloroform solution is extracted With aqueous sodium bicarbonate, and the bicarbonate solution is acidified and extracted with chloroform. The chloroform solution is dried over magnesium sulfate and concentrated under reduced pressure to an oil. The a,' -bis[methy]mercapto] butyric acid so obtained has a refractive index: n =1.5276 and a neutralization equivalent of 183 (theory 180). p

The a,'y-dibromobutyric acid is prepared as follows: 280 gm. of y-butyrolactone and 10 ml. of phosphorous tribromide are combined and heated to 100 C. with stirring. Bromine is added to the mixture for about 2.5 hours. During the first 1.5 hours the temperature is maintained at about -l30 C. The temperature is then lowered to 90 C. to prevent evolution of hydrogen bromide. After the bromine addition is complete the reaction mixture is heated at 90-95 C. for about 2 hours and then cooled. The solution contains O6,'Y'dibrOln0 butyricv acid.

Production of methyl-ayy-biflmethylmercapto] butyrate impure methyl-a,' -bis[methylmercapto] butyrate is dissolved in ether and washed with aqueous sodium bicarbonate, The ether extract isYWashed with watendried over anhydrous magnesium sulfate, and concentrated under diminished pressure to an oil consisting of methylec,'y-bis[methylmercapto] butyrate.

EXAMPLE n Production of org-bis[ethyimercapto] butyric acid Production of ep bis[butyimcrcapio] butyric acid A solutionof sodium butylmercaptide is prepared by dissolving 27 gm. of sodium methoxide in 300 ml. of cold methanol and adding 45 gm. of butylmercaptan with cooling and stirring. To the cooled solution is added 39 gm. of ayy-diblOmObLlWliC acid and the mixture allowed to stand for several hours. After removing the solvent under diminished pressure 100 ml. of water is added to the residue of soditim-a,' -bis[butylmercapto] butyrate. Concentrated hydrochloric acid is added to pH 3 and unreacted butylmercaptan removed by steam distillation. The residue containing a,' -bis[butylmercapto] butyric acid is added to chloroform and extracted with aqueous sodium bicarbonate. The purified product is isolated by acidification of the aqueous solution, extraction with chloroform and removal of the solvent.

Production of ethyl-e,'y-bis[butylrnercapto] bzityrate About 0.1 mole of a,y-bis[butylmercaptol butyric acid is added slowly to 0.15 mole of thionyl chloride. 7 After the reaction has terminated excess thionyl chloride is removed under diminished pressure leaving a,'ybisEbutylmercapto] butyryl chloride. The acid chloride is cooled, combined with an excess of ethanol and warmed to 5070 C. The ethyl ester of u,-y-bis[butylmercapto] butyric acid is isolated from the reaction mixture by removing excess ethanol.

EXAMPLE IV Production of a,'y-bis[phenylmercapt0] butyric acid Production met'Lyl-ayy-bislplienylmercapto] butyrate 0.2 mole of tm/ bis [phenylmercapto] butyric acid and 0.3'mole of thionyl chloride are reacted under anhydrous conditions at a slightly elevated temperature. Upon termination of the reaction the mixture is distilled room temperature under diminished pressure to remove excess thionyl chloride leaving a residue consisting of ctky-bislphenylmercaptolbutyryl chloride. The acid chloride is reacted with an excess of methanol to produce the methyl ester of iv -bis [phenylmercapto] butyric acid.

8 The product is isolated and purified by conventional methods;

r p a EXAMPLE-V Production of a,'y-bis[benzylmercapt0] butyric acid To a solution of 81 gm. of sodium methylate in 800 ml. of methanol is added 186 gm. of benzylmercaptan. About 123 gm. of w' -dibromobutyric acid'is added drop- Wise to the mixture, is refluxed for about one hour, the

, and dried over magnesium sulfate.

methanol removed and the residue consisting of sodiumtxy nis[bcnayimercapto] butyrate added to ice water. The aqueous solution is acidified with hydrochloric acid giving a,'y-bis[benzylmercapto] butyric acid as an oil. The product is purified by disolving it in ether, extracting with aqueous potassium bicarbonate, acidifying the aqueous solution with acid and extracting the product with ether. The purified orgy-hi8 [benzylmercapto] butyric acid is recovered by removing the ether under reduced pressure.

Production of ethyl-oi y-bis[benzylmercapto] butyratc Approximately 0.2 mole of thionyl chloride is added to 0.15 mole of cooled a 'y-bis[benzylmercapto] butyric acid with stirring. After the initial vigorous reaction the mixture is allowed to warm to room temperature, stand for 1 hour and the excess thionyl chloride removed by evaporation under diminished pressure. The product is treated with ethanol and concentrated under diminished pressure. The residue is primarily ethyl-u,'y-bis[benzylmercaptol butyrate. t is purified by dissolving the prodnot in chloroform, washing the chloroform solution with aqueous sodium bicarbonate and subsequently removing the solvent.

EXAMPLE VI Production of e-methylmercapto-y-butyrolactone A solution of 20.3 gm. of sodium methylmercaptide in 225 m1. of methanol is added to a cooled solution of 37.7 gm. of a-bromo-y-butyrolactone in 50 ml. of methanol. After standing at room temperature for about one hour the methanol from the reaction mixture is distilled off under diminished pressure and replaced with ml. of water. The impure ot-methylmercapto-y-butyrolactone which separates out as an oil is extracted with chloroform. The resulting chloroform solution is Washed with Water The chloroform is removed under diminished pressure leaving an oil which is distilled to give a-methylmercapto-vbutyrolactone boiling at 64.0-66.5 C. 0.1 mm., n =1.5040. The infrared spectrum discloses a lactone band at 5.68 and absorption in the 1315 n region which is indicative of the CS-C bond.

Production of the sodium methylmercaptide addition product of oc-methyImcrcapto-y-butyrolactone A solution of 10.8 gm. of a-methylmercapto-'y-butyrolactoue in 20 ml. of toluene is added to a stirred suspen- Production 0 ot,'y-bis[methylmercapt0] butyric acid from ,thasodium methylmercaptide addition product of etmethylmercapto-y-butyrolactone The sodium methylmercaptide addition product of 0&- methylmercapto-v-butyrolactone prepared above is heated at about 165l70 C. for thirty minutes. After cooling the fused mixture to about 100 C. it is dissolved in ml. of 'water and the solution adjusted to pH 3 with hydrochloric acid. The a,-.y-bis[methylmercapto] butyric acid separates from solution and is extracted with chloroform. The chloroform solution is extracted with aqueous sodium bicarbonate, the aqueous extract acidified with hydrochloric acid and extracted with chloroform. The

I chloroform extract is washed with water and dried over magnesium sulfate. The chloroform is removed by evaporation under diminished pressure leaving substantially pure otfl-biS [methylmercapto] butyric acid as a heavy'oil, B. P. l54 l58 C./0.l mm., n 5:1.5267, neutralization equivalent=184 (theory 180). The infrared spectrum in carbon disulfide indicates a carboxylic acid with a C=O stretch at 5.85 a

Production of methyl-dgy-bis[methylmercapto] butyrate An excess of diaz omethane in ether is added to a cold solution of 1.3 gm. of a -bis [methylmercapto] butyric acidin ml. of anhydrous ether. After standing 'at room temperature for 10 minutes the ether is removed under reduced pressure. The resulting oil is distilled under diminished pressure to give methyl-oi,'y-bis [methylmercapto] butyrate, B. P. 72-74" C./0.13 mm., 22 145097.

EXAMPLE v11 Production of the potassium ethylmercaptide addition product of u-methylmercupto-v-butyrolactone .A solution of 0.1 mole of a-methylmercapto -butyrolactone, prepared as in Example VI, in ml. of toluene is added with stirring to a suspension of 0.12 mole of potassium ethylmercaptide in 50 ml. of toluene. The mixture is stirred for several hours at about 20-40 C. and the toluene removed under reduced pressure to obtain the potassium ethylmercaptide addition product of w methylmercapto- -butyrolactone.

Production of ot-methylmercaptoy-ethylmercapto' butyric acid The potassium ethylmercaptide addition product of amethylmercaptorbutyrolactone prepared above is-heated at ISO-180 C. for 45 minutes, cooled and dissolved in water. The aqueous solution of potassium-a-me thylmer- 'capto-v-ethylmercapto butyrate is acidified to pH 3 with concentrated hydrochloric acid and extracted with chloroform. The chloroform solution is extracted with aqueous sodium bicarbonate, the aqueous extract is acidified and finally extracted with ether. The ot-methylmercaptoethylmercapto butyric acid is isolated by removing the ether and is purified by distillation under. diminished pressure.

EXAMPLE VIII Production of ot-propylmercapto y-butyrolactone Production of the sodium ethylmercaptide addition product of a-propylmercapto-v-butyrolactone The a-propylmercaptow-butyrolactone produced according to the method described above is reacted with an equivalent amount of potassium ethylmercaptide in 7 0 ml. of toluene. The mixture is stirred overnight at room temperature and the sodium ethylmercaptide addition product of u-propylmercaptow-butyrolactone recovered by distilling ofi the solvent.

Production of oi-propylmsrcopto-y-ethylmercapto butyric acid The sodium ethylmercaptide addition product of oc-PI'O- pylmercaptow-butyrolactone from above is fused at about 170 C. for about 30 minutes, cooled and added to 250 ml.

- of water. The aqueous solution of sodium a-propylmercapto-y-ethylmercapto butyrate is acidified and extracted with ether. By removing t irgetherthere is obtained apropylmercapto-- -ethylmercapto butyric acid,

' EXAMPLE IX Production of a-bcn'zylrncrcoptowbutyrolactone About 54 gm. of sodium inethylate is dissolved in 400 ml. of cold methanol and combined with a solutionof 124 gm. of benZylmercaptan in 200 'ml.-of methanol. After standing for 15 minutes 164gm. of nt-bromo- -butyrolactone is added to the mixture with cooling. The mixture is allowed to stand at room temperature for about one hour, filtered and the solvents removed under reduced pressure. The residue is added to 300 ml. of water, extracted with chloroform and the chloroform removed. The residue is distilled to give a-benzylmercapto -butyrolactone, B. P. 137440 c./0.03 mm., n 1.5752. Y

' Production of the sodium methylmercaptide addition product of a-benzylmercapto-v-bun rolactone To a stirred solution of 0.4 mole of a-benzylmercapto-y butyrolactone in 40 ml. of toluene is added a suspension of 0.5 mole of sodium methylmercaptide in 150 ml. of benzene. The mixture is maintained at 20-40 C. for one hour and the benzene removed under reduced pressure to give the sodium methylmercaptide addition product of abenzylmercapto-y-butyrolactone.

Production of a-benzylmercapto-y-methylmercapto butyric acid Approximately 0.1 mole of the sodium methylmercaptide addition product of u-benzylmercaptow-butyrolactone is heated to'170--l80 C. for two hours, cooled and added to water. The aqueous solution of sodium a-benzylmercapto-y-methylmercapto butyrate is acidified, extracted with ether and the ether removed to give a benzylmercapto-y-methylmercapto butyric acid.

EXAMPLE X Production of a-'y-bis(allylmercapto) butyric acid About 1.5 mole of allyl bromide is added dropwise to a stirred refluxing solution of 1.5 moles of thiourea in 500 ml. of methanol over a period of fifteen minutes, and refluxing is then continued for an additional thirty minutes. A solution of three moles of potassium hydroxide in methanol is next added rapidly and the solution refluxed for another twenty minutes.

The solution of potassium allylmercaptide thus prepared is cooled and 0.5 mole of u,'y-dibromobutyric acid is added. The mixture is allowed to stand at room temperature overnight, and then concentrated under reduced pressure. The residue is diluted with water and acidified with concentrated HCl. The desired product is isolated from the-acidic solution by extraction with chloroform and subsequent removal of the solvent under reduced pressure. The product had the following physical constants: Neut. equiv. 247 (calc. 232) mol. wt. (ebulliometric) 241:: 4 (calc. 232); sulfur 25.68% (calc. 27.60%).

Production of a,'y-bis(allylmercap to) butyryl chloride A benzene solution containing 13 g. of a,'y-bis(allylmercapto) butyric acid is cooled in an ice bath and 5 ml. of thionyl chloride added. The mixture is stirred with cooling for one hour, the excess thionyl chloride removed under reduced pressure and u,'y-bis(allylmercapto) butyryl chloride purified by distillation: B. P. ISO-137 C./12 mm.; n =l.5456.

Production of methyl-a,'y-bis(aliylmercapto) butyrate Twenty ml. of cold methanol is added to 4.0 g. of 04,7- bis(allylmercapto) butyryl chloride and the mixture allowed to stand. The excess alcohol is removed under reduced pressure and the residue distilled to give methyla- -bis(allylmercapto) butyrate: B. P. -82 C./ .05 mm.; n =1.5280.

a 1 l Whatis elaimed'is:

1. The process for the production of a compound having the formula CHr-CHa-OH -GOOY I R SR which comprises fusing a compound of the formula CH3CH2 V GH-SR H 'OY SR wherein in each occurrence R is selected from the group which comprises fusing a compound of the formula v CHFCHI sir sisting of lower alkyl, lower alkenyl, phenyl and benzyl radicals, R is a lower alkyl radical and Y is selected from the group consisting of alkali metal, alkaline earth metal and ammonium radicals.

3. The process which comprises fusing a member of the group consisting of ammonium, alkali metal and alkaline earth metal lower alkylmercaptide addition products ofa-lower alkylmercapto-y-butyrolactone at a temperature of about ISO-200 C. to produce the corresponding salt of ayy-bisllower alkylmercaptolbutyric acid.

4. The process according to 'claim 3 in which the salt is hydrolyzed to the corresponding a,-, -bis[lower alkylmercaptolbutyric acid.

5. The process which comprises fusing the sodium methylmercaptide addition product of a-methylmercapto- 'y-butyrolactone and treating the resulting product with acid to produce un -bis[methylmercaptolbutyric acid.

References Cited in the file of this patent UNITED STATES PATENTS 1,715,795 Staudinger June 4, 1929 1,748,527 Staudinger Feb. 25, 1930 2,193,858 Buchman Mar. 19, 1940 2,422,246 Lazier et al. June 17, 1947 2,530,348 Britton et al. NOV. 14, 1950 2,539,428 Jansen Jan. 30, 1951 2,568,636 Japs Sept. 18, 1951 2,752,373 Acker June 26, 1956 

1. THE PROCESS FOR THE PRODUCTION OF A COMPOUND HAVING THE FORMULA 